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GWAS Turns up Variants Associated with Childhood Obesity

NEW YORK (GenomeWeb News) – An international research consortium has conducted what researchers say is the largest-ever genome-wide association study of common childhood obesity, identifying at least two new variants associated with the condition.

The study, conducted by the Early Growth Genetics (EGG) Consortium and led by researchers at the Children's Hospital of Philadelphia, analyzed 14 previous studies from the US, Canada, Australia, and Europe that included 5,530 cases of childhood obesity and 8,300 control subjects, all of European ancestry. The researchers found two new loci — one near the OLFM4 gene on chromosome 13 and the other within the HOXB5 gene on chromosome 17 — associated with obesity among individuals under the age of 18. They defined obesity as those subjects being above the 95th percentile in body mass index.

The results of the study were published online yesterday in Nature Genetics.

The researchers noted that although many genetic loci have been implicated in body mass index or obesity phenotypes in genome-wide association studies, those studies focused on adults.

For example, they noted that the Genetic Investigation of ANthropometric Traits (GIANT) Consortium has already confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with BMI in a study involving a total of 249,796 individuals. But, the EGG researchers said that the loci from the GIANT studies "only account for a small fraction of the heritability that is known to contribute to obesity."

In their meta-analysis of 2.7 million SNPs from the 14 GWAS data sets for childhood obesity, the researchers said that seven loci reached genome-wide significance: FTO, TMEM18, POMC, MC4R, FAIM2, TNNI3K, and SEC16B. All of these loci had previously been identified through GWAS for adult BMI.

In an effort to replicate results in multiple independent existing data sets, they then tested these eight SNPs in nine study groups that had a comparable set of affected subjects with BMI distributed normally from the 95th percentile upward (a total of 2,818 cases and 4,083 controls). The researchers found two loci that yielded consistent evidence of association, one near OLFM4 and the other within the HOXB5 gene.

Those two loci also yielded evidence of association in the GIANT Consortium's study, which was published in Nature Genetics in October 2010.

"Of note, in addition to OLFM4 and HOXB5, the GIANT Consortium data support associations with three more of the eight loci initially taken forward to the replication stage, namely rs4864201 at BC041448, rs4833407 at ALPK1 and rs2300095 at MTOR-ANGPTL7, despite these signals not formally replicating in the main defined overall pediatric setting, suggesting that these loci should be studied further to fully understand their role in the pathogenesis of obesity as a whole," the study authors wrote.

"This is the largest-ever genome-wide study of common childhood obesity, in contrast to previous studies that have focused on more extreme forms of obesity primarily connected with rare disease syndromes," lead investigator Struan Grant, associate director of the Center for Applied Genomics at the Children's Hospital of Philadelphia, said in a statement. "As a consequence, we have definitively identified and characterized a genetic predisposition to common childhood obesity."

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